Stem cells are immature, uncommitted cell types that possess the abilities to:
- Self-renew indefinitely by symmetric cell division;
- Undergo asymmetric cell division also, generating another stem cell and a daughter cell capable of differentiating into multiple mature cell types.
By definition, a cell’s level of lineage commitment is inversely related to its potency. Pluripotent stem cells are capable of generating all cell types in the developing and adult body (embryonic stem [ES] and induced pluripotent stem [iPS] cells are two examples), while multipotent somatic stem cells are committed to a certain developmental lineage. During differentiation, stem cells undergo lineage commitment and lose their self-renewal capacity, thereby becoming progenitor cell that are further restricted in potency. Progenitor cells undergo limited proliferation prior to terminal differentiation to yield a mature cell type. A variety of distinct stem and progenitor cells classes exist, each with particular characteristics that make them attractive for certain potential therapeutic purposes; here, we will discuss specific cell types in the contexts to which they appear best suited.
Stem cell transplantation therapy is of clinical interest because of its potential to treat degenerative conditions that are currently incurable (although in some cases manageable), such as glaucoma.
There are at least two mechanisms by which stem cell transplantation might be applied to glaucoma.
The most significant, prospective therapeutic power of stem cells lies in their ability to generate new cells of many types and to effect tissue regeneration.
Thus, it is conceivable that stem cells may offer therapeutic hope for glaucoma via selective cell replacement of retinal glaucoma cells (RGCs) and optic nerve regeneration to restore function.
In addition, certain types of stem cells possess protective properties capable of alleviating disease progression and promoting survival of endogenous tissue. This is proposed to occur through a variety of mechanisms, some of which are cell or tissue specific. Ideally, RGC neuroprotection would serve as an adjunct with existing ocular hypotensive therapies to prevent progressive glaucomatous vision loss.
Transplantation of stem cells that secrete relatively high levels of NTFs is likely to be the most applicable short-term cell-based therapy for glaucoma.
Neural stem cells are reportedly capable of reducing CNS inflammation, thereby promoting functional recovery in a range of neurodegenerative diseases. If inflammation proves integral to glaucomatous RGC loss, then it is conceivable that the antiinflammatory properties of transplanted stem cells could confer benefit in glaucoma.
Other purported mediators of glaucomatous neurodegeneration include oxidative stress, vascular insufficiency and excitotoxicity. There is evidence that some stem cells secrete factors that could modulate these processes.
While many stem cell transplantation studies have demonstrated histological and functional improvement in various neurodegenerative disease models, the exact mechanism(s) and pathway(s) underlying this effect remain, for the most part, elusive. It has been hypothesized that NTF secretion, anti-inflammatory modulation and many other processes play key roles, however, definitive mechanisms specific to RGC survival in glaucoma should be elucidated prior to clinical translation. This will facilitate full comprehension of a novel treatment, and may also reveal unappreciated mechanisms of RGC neuroprotection that may be amenable to manipulation via alternate intervention.
At present, it is unclear whether it may be more advantageous to transplant neural or retinal stem cells, RGC precursors (committed to an RGC fate but not yet fully differentiated) or mature RGCs for RGC replacement.
